This application proposes to establish a Medication Development Unit (MDU) in Los Angeles, dedicated to rapidly evaluating potential pharmacotherapeutic agents for the treatment of cocaine and methamphetamine abuse and dependence. The proposed MDU, comprising two clinical trial components, and a core, replaces the existing P50 Medication Development Center and will sharpen the research focus on stimulants. The Core will provide central support and be responsible for personnel management, budget, purchasing and contracts, central laboratory, recruitment, quality assurance, training, data management and statistical support, dissemination of research results, and coordination of local, national and international training activities and scientific presentations. The Core is itself embedded within the greater Los Angeles Addiction Research Consortium, facilitating resource sharing and reducing the overall cost. Both clinical trial components will take advantage of refinement of the current rapid cocaine medications evaluation strategy to screen medications suitable for further development. The methamphetamine component will, in addition, address neurocognitive dysfunctions specific to chronic methamphetamine abuse. All studies will utilize central recruitment; uniform operating procedures; standardized CRFs to the extent possible; common outcome measure, data collection procedures, quality assurance, data analysis and interpretation, and dissemination of study results. Each study will recruit 120 subjects randomized to three groups (35 to each active medication arm and 50 to placebo). Each component will evaluate four medications (or combinations) during the period of the grant. These medications will be selected with input from the Medications Development Division's (MDD) Compound Identification Committee. These studies will use the psychosocial treatment platform utilized extensively in our clinical trials. Completion of this work will contribute toward the development of medications for stimulant dependence and toward reduction in HIV risk behaviors. Medications showing promise will be presented to NIDA as candidates for further development through larger samples or multi-site studies. The MDU will also contribute toward establishing, national, and international resource for training, research, and dissemination of research results.